Visually impairing cataract is the leading cause of preventable blindness in the world. Presently, the only known treatment for cataract is the surgical removal of the opacified lens of the affected eye and replacement with an artificial intraocular lens, typically including an intraocular lens optic and haptics (“IOL”). Technological advances in cataract surgery with IOL implantation have made cataract surgery among the most effective surgical procedures.
Now referring primarily to FIGS. 1 and 2, which show a top view and a cross section view of a phakic eye (1). The most common technique of cataract surgery may be extracapsular cataract extraction (“ECCE”) which involves the creation of an incision (2) near the outer edge of a cornea (3) and a circular opening (4)(shown in FIGS. 3 and 4) in an anterior lens capsule (5)(also referred to as the “anterior capsule”) through which the opacified natural lens (6) can be removed from the lens capsule (7)(also referred to as the “capsular bag”). Now referring primarily to FIGS. 3 and 4 which show a top view and a cross section view of a pseudophakic eye (8), the lens capsule (7) anchored to the ciliary body (9) through the zonular fibers (10) can be left substantially intact. An IOL (11) can then be placed within the lens capsule (7) through the circular opening (4) in the anterior capsule (5). The IOL (11) can be acted on by zonular forces exerted on the outer circumference (12) of the lens capsule (7) which establishes the location of the IOL (11) within the lens capsule (7). The intact posterior capsule (13) acts as a barrier to the vitreous humor (14) within the posterior segment of the phakic or pseudophakic eye (1)(8).
The most frequent complication to ECCE and other methods of cataract surgery can be opacification of the posterior capsule (13). Posterior capsule (13) opacification (“PCO”) results from the migration of residual lens epithelial cells (“LEC”)(16) between the IOL (11) and the surface of the posterior capsule (13) subsequent to cataract surgery. The residual LECs (16) once located between the IOL (11) and the surface of the posterior capsule (13) can proliferate leading to clouding of the normally clear posterior capsule (13). Clouding of the posterior capsule (13) can decrease visual acuity, if the opacification occurs within the visual axis (15) of the pseudophakic eye (8).
Visually significant PCO requires an additional surgery to clear the visual axis (15) of the pseudophakic eye (8). Presently, the most widely utilized procedure to clear the visual axis (15) of PCO may be Neodymium: Yttrium-Aluminum-Garnet (“Nd:YAG”) laser capsulotomy. However, there may be substantial problems with this procedure such as IOL (11) damage, postoperative intraocular pressure spikes, vitreous floaters, cystoid macular edema, retinal detachment, and IOL (11) subluxation, or the like. Additionally, pediatric patients can be difficult to treat and a delay in treatment can lead to irreversible amblyopia. Many underdeveloped countries do not have access to a Nd:YAG laser and the cost can be prohibitive.
Prevention or inhibition of PCO fall into two broad categories: mechanical and pharmacological. Mechanical mechanisms to inhibit PCO have primarily focused on configuration of the IOL (11). Configuring the IOL (11) to include a sharp posterior edge may provide a structural barrier to the migration of residual LECs (16) between the IOL (11) and the surface of the posterior capsule (13). Cleary et al., Effect of Square-edged Intraocular Lenses on Neodymium: YAG Laser Capsulotomy Rates in the United States, J. Cataract & Refractive Surgery, Vol. 33, p. 1899-1906 (November 2007). However, while introduction of square edged IOLs (11) appears to have reduced incidence of PCO, a review of Medicare claims data from 1993 to 2003 evidences that the number of laser capsulotomies performed in the United States to treat PCO in recipients of square edged IOL (11) remains substantial.
Pharmacological mechanisms have been proposed as a way to inhibit or prevent PCO. The effect of topical treatment with nonsteroidal anti-inflammatory drugs (“NSAIDs”) such as diclofenac and indomethacin after phacoemulsification do not appear to inhibit PCO. Inan et al., Effect of Diclofenac on Prevention of Posterior Capsule Opacification in Human Eyes, Can J Ophthalmol, 41; 624-629 (2006). Additionally, the majority of pharmacological agents tested in-vitro for inhibition of migration and proliferation of LECs (16) are antimetabolites and antimitotics which have not been used clinically because of their toxic side effects. Inan U U, Ozturk F, Kaynak S, et al. Prevention of Posterior Capsule Opacification by Intraoperative Single-dose Pharmacologic Agents, J Cataract Refract Surg, 27:1079-87(2001); Inan U U, Ozturk F, Kaynak S. Ilker S S, Ozer E, Güder, Prevention of Posterior Capsule Opacification by Retinoic Acid and Mitomycin, Graefes Arch Clin Exp Ophthalmol 239: 693-7(2001); Cortina P, Gomez-Lechon M J, Navea A, Menezo J L, Terencio M C, Diaz-Llopis, M, Diclofenac Sodium and Cyclosporine A Inhibit Human Lens Epithelial Cell Proliferation in Culture, Graefes Arch Clin Exp Ophthalmol 235: 180-5(1997); Ismail M M, Alio J L, Ruiz Moreno J M, Prevention of Secondary Cataract by Antimitotic Drugs: Experimental Study, Ophthalmic Res, 28:64-9 (1996); Emery J., Capsular Opacification After Cataract Surgery, Curr Opin Ophthalmol, 10:73-80 (1999); Hartmann C, Wiedemann P, Gothe K, Weller M, Heimann K, Prevention of Secondary Cataract by Intracapsular Administration of the Antibiotic Daunomycin, Ophthalmologie, 4:102-6 (1990).
Also, available is a sealed capsule irrigation device which functions to allow selective irrigation of the lens capsule (7) with LEC (16) inhibiting pharmacologic agents. Maloof A J, Neilson G, Milverton E J, Pandy S K, Selective and specific targeting of lens epithelial cells during cataract surgery using sealed-capsule irrigation, J Cataract Refract Surg, 29:1566-68 (2003). It is not clear, however, that use of the device can be reduced to routine practice. Problems relating to incomplete seal of the lens capsule (7) resulting in leakage of potentially toxic chemicals into the anterior chamber (17) of the pseudophakic eye (8), rupture of the lens capsule (7) during manipulation of the irrigation device, difficulty in assessing kill of LECs (16) within the lens capsule (7) and an increase in the duration of routine cataract surgery limit the usefulness of the irrigation device.
Another prominent problem with routine cataract surgery and other surgical procedures such as retinal surgery, cornea transplant surgery, glaucoma surgery, or the like, can be postoperative administration of antibiotics to prevent endophthalmitis. Topical antibiotic and anti-inflammatory eye drops represent the mainstay of drug delivery for intraocular surgery. However, there has yet to be a prospective randomized study showing that topical antibiotics prevent endophthalmitis. Also, because the human cornea acts as a natural barrier to biologic and chemical insults, intraocular bioavailability usually requires frequent dosing regimens for each medication. Topical drops can be difficult for young and elderly patients and the drop schedule can be cumbersome and confusing particularly when following surgery each eye (1)(8) is on a different drop schedule. These difficulties can result in non-compliance with serious consequences such as endophthalmitis, glaucoma, and cystoid macular edema. Recent prospective studies supporting the use of intracameral antibiotic injections for prophylaxis of endophthalmitis have stirred debate regarding the risks associated with this method of antibiotic prophylaxis including the short duration of protective effect (possibly less than 24 hours), the introduction of potentially contaminated substances in the anterior chamber (17), endothelial cell toxicity, toxic anterior segment syndrome, dilutional and osmolarity errors during mixing, and the like. Also, the systemic administration of drugs for treatment of localized ocular conditions may not be preferred because of the inefficiency associated with indirect delivery of the drugs to a target organ.
Recognizing these disadvantages of conventional delivery of antibiotics and other drugs to the eye (1)(8), external ocular inserts were developed utilizing biologically inert materials to act as a reservoir for slow release of the drug. These external ocular inserts may be placed within the upper and lower conjunctival fornix of the eye (1)(8) to achieve a uniform sustained rate of release of drug in therapeutically effective amounts. However, patients can be intolerant of these devices due to difficulty in insertion and removal and mild to moderate conjunctival irritation during use which may explain why external ocular inserts have not been widely accepted in clinical practice.